New results show how serotonin shapes behavior in negative situations

New results show how serotonin shapes behavior in negative situations

In a recent study inNature communicationResearchers increased synaptic serotonin using a selective serotonin releasing agent (SSRA), fenfluramine, to study the effects on human behavior.

background

Neuroscience research focuses on the function of central serotonin (5HT) in human behavior, particularly the influence of selective serotonin reuptake inhibitors (SSRIs). Serotonin is required for multiple actions including eating, sexual function, and goal-directed cognition.

It is difficult to determine the causal relationship between increased synaptic 5-HT and behavior in humans via SSRIs due to complicated effects of SSRIs on 5-HT and colocalized neurotransmitter systems. A low dose of fenfluramine, approved for the treatment of Dravet epilepsy in 2020, directly and rapidly increases synaptic 5-HT without altering extracellular dopamine concentrations in mood control areas.

About the study

In the present study, researchers examined the effects of direct synaptic serotonin (5-HT) with fenfluramine in humans, focusing on unpleasant processing, behavioral inhibition and memory. They investigated whether fenfluramine would differentiate the behavior from that observed with tryptophan deprivation.

Researchers included 53 people (mean age 20 years and 32 female) who received fenfluramine hydrochloride 15 mg twice daily (intervention group, n = 26) or placebo (n = 27) for eight days. They recruited eligible people between June 2021 and June 2022, excluding those who were pregnant and trying to become pregnant, breastfeeding, and those with a recent history of drug use. All participants spoke English fluently and had body mass index (BMI) values ​​between 18 and 30.

Researchers used the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) criteria and assessed cardiovascular, hepatic and kidney health to screen individuals. At baseline, participants completed various emotional and cognitive tasks and questionnaires. The researchers performed immunoassays to measure fenfluramine-related salivary cortisol changes. They used linear mixed effects modes and analysis of covariance (ANCOVA) to derive results.

At both visits (baseline and eight days later), participants completed questionnaires assessing mood, anxiety, depression, subjective cognitive function, and adverse effects. Questionnaires included the Beck Depression Inventory-II (BDI), Perceived Deficit Questionnaire-Depression (PDQ-D), Spielberger State-Trait Anxiety Inventory (STAI-T), Positive and Negative Affect Schedule (Panas), and Visual Analogue Scale (Vas).

Participants performed the Auditory Verbal Learning Task (AVLT), the Affective Interference GO/No-Go Task, the Verbal N-Back Task, the Probabilistic Instrumental Learning Task, the Oxford Memory Task, and the Contextual Cueing Task to measure implicit learning and visual search ability.

The AVLT task measures declarative memory encoding and retrieval; The affective interference GO/No-Go task measured behavioral inhibition under affective interference; the Verbal N-Back measured complex verbal working memory; The probabilistic instrumental learning task measured reward and loss sensitivity during instrumental learning; The Oxford Memory task measured visual working memory; and the contextual cueing task measured implicit learning and visual search ability.

Results

The study found that increasing synaptic serotonin decreases reinforcement sensitivity to unpleasant outcomes while improving behavioral inhibition and altering impulse control bias during aversive interference or exposure to unwanted emotional probes. Increasing synaptic serotonin improved memory for neutral verbal information.

Fenfluramine allocation decreased optimal choice in loss trials and reward circumstances, implying that increased synaptic 5-HT reduced outcome sensitivity in loss trials. However, learning rates were not significantly different between groups. Fenfluramine administration also increased option selection time under loss conditions and showed a relative reduction in loss sensitivity.

The net increase in synaptic 5-HT reduces gain sensitivity to loss outcomes, whereas 5-HT depletion improves loss sensitivity. Fenfluramine administration improved response inhibition and cautious decision making on go trials, but there was no significant group effect on go trial accuracy. Increasing synaptic 5-HT reduced impulsivity selection across all task circumstances, with the highest reduction found when adverse emotional distractions were present.

The study discovered that increasing synaptic 5-HT improves verbal memory processing. However, there was no significant group effect on the total number of accurately recalled targets during extended oral working memory processing. Fenfluramine allocation resulted in faster recall of correct targets and greater overall accuracy in delayed recall.

The team found no significant group effect for learning trials, word repetitions, intrusions, or visual working memory tasks. The placebo group outperformed the fenfluramine group, although not statistically significantly. Gender had no influence on the effects of fenfluramine administration on task performance.

Diploma

The study found that increasing synaptic serotonin directly influences human behavior and influences decision-making in unpleasant and neutral circumstances. Higher serotonin reduces sensitivity to loss consequences and improves impulse control during behavioral inhibition in adverse situations. Higher serotonin improves behavioral inhibition by promoting careful decision making and memory retention under neutral conditions.

The study results have implications for central serotonin function hypotheses and highlight the potential of SSRA as an experimental probe. Exploring its therapeutic potential could help us better understand serotonin's involvement in human behavior and mental etiology.

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